Aneuploidy, the loss or gain of chromosomes, is the leading cause of human pregnancy failure and birth defects. Most aneuploidy arises from maternal nondisjunction, but its etiology remains obscure. Environmental factors have long been suspected to play a role but, until recently, this has not been substantiated by direct evidence. Recent studies in our laboratory suggest that exposure to the estrogenic chemical, bisphenol A (BPA) during pregnancy dramatically increases the frequency of chromosomally abnormal eggs and embryos in the mouse. Because humans are exposed to BPA on a daily basis, these findings have serious implications for human reproductive health. The studies outlined in this application will use mouse models to test the effects of fetal BPA exposure on reproductive lifespan in the female and examine the mechanisms by which BPA exerts its effects on the early stages of oogenesis. In addition, we will translate our findings from mice to humans by directly studying human fetal oocytes to determine if BPA similarly impacts early oogenesis in humans. Lastly, we will test the effect of genetic variation on the ability of biologically active BPA to reach specific tissues and on the tissue response to BPA. The combined data from these studies will enhance our understanding of the risk to human fertility posed by this chemical. PUBLIC HEALTH RELEVANCE: These studies will assess the effects on human reproductive health of bisphenol A (BPA), a member of a class of chemicals known as endocrine disrupting chemicals. Specifically, the studies outlined in this application focus on BPA-induced effects on gametogenesis in female mice and - for the first time - directly address the possibility that BPA exposure affects gamete production in humans as well.